Selection and optimization of hits from a high-throughput phenotypic screen against Trypanosoma cruzi.

BACKGROUND Inhibitors of Trypanosoma cruzi with novel mechanisms of action are urgently required to diversify the current clinical and preclinical pipelines. Increasing the number and diversity of hits available for assessment at the beginning of the discovery process will help to achieve this aim. RESULTS We report the evaluation of multiple hits generated from a high-throughput screen to identify inhibitors of T. cruzi and from these studies the discovery of two novel series currently in lead optimization. Lead compounds from these series potently and selectively inhibit growth of T. cruzi in vitro and the most advanced compound is orally active in a subchronic mouse model of T. cruzi infection. CONCLUSION High-throughput screening of novel compound collections has an important role to play in diversifying the trypanosomatid drug discovery portfolio. A new T. cruzi inhibitor series with good drug-like properties and promising in vivo efficacy has been identified through this process.

[1]  David M. Shackleford,et al.  Design, structure-activity relationship and in vivo efficacy of piperazine analogues of fenarimol as inhibitors of Trypanosoma cruzi. , 2013, Bioorganic & medicinal chemistry.

[2]  J. Altcheh,et al.  Efficacy of voriconazole in a murine model of acute Trypanosoma cruzi infection. , 2013, The Journal of antimicrobial chemotherapy.

[3]  Ana Rodriguez,et al.  Antitrypanosomal lead discovery: identification of a ligand-efficient inhibitor of Trypanosoma cruzi CYP51 and parasite growth. , 2013, Journal of medicinal chemistry.

[4]  A. Talvani,et al.  Fexinidazole: A Potential New Drug Candidate for Chagas Disease , 2012, PLoS neglected tropical diseases.

[5]  J. Baell,et al.  Identification of Compounds with Anti-Proliferative Activity against Trypanosoma brucei brucei Strain 427 by a Whole Cell Viability Based HTS Campaign , 2012, PLoS neglected tropical diseases.

[6]  M. J. Yunta,et al.  Phthalazine derivatives containing imidazole rings behave as Fe-SOD inhibitors and show remarkable anti-T. cruzi activity in immunodeficient-mouse mode of infection. , 2012, Journal of medicinal chemistry.

[7]  M. K. Kathiravan,et al.  The biology and chemistry of antifungal agents: a review. , 2012, Bioorganic & medicinal chemistry.

[8]  Michelle R. Arkin,et al.  Diverse Inhibitor Chemotypes Targeting Trypanosoma cruzi CYP51 , 2012, PLoS neglected tropical diseases.

[9]  G. Franco,et al.  Unequivocal Identification of Subpopulations in Putative Multiclonal Trypanosoma cruzi Strains by FACs Single Cell Sorting and Genotyping , 2012, PLoS neglected tropical diseases.

[10]  B. Hall,et al.  Benznidazole-Resistance in Trypanosoma cruzi Is a Readily Acquired Trait That Can Arise Independently in a Single Population , 2012, The Journal of infectious diseases.

[11]  M. J. Abbott,et al.  Analogues of fenarimol are potent inhibitors of Trypanosoma cruzi and are efficacious in a murine model of Chagas disease. , 2012, Journal of medicinal chemistry.

[12]  Edward W. Tate,et al.  Selective Inhibitors of Protozoan Protein N-myristoyltransferases as Starting Points for Tropical Disease Medicinal Chemistry Programs , 2012, PLoS neglected tropical diseases.

[13]  M. Llewellyn,et al.  The revised Trypanosoma cruzi subspecific nomenclature: rationale, epidemiological relevance and research applications. , 2012, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[14]  A. Chatterjee,et al.  Back to the Future: Lessons Learned in Modern Target-based and Whole-Cell Lead Optimization of Antimalarials , 2012, Current topics in medicinal chemistry.

[15]  Ian H. Gilbert,et al.  Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors , 2011, Journal of medicinal chemistry.

[16]  Joshua A. Bittker,et al.  Identification of small-molecule inhibitors of Trypansoma cruzi replication. , 2011, Bioorganic & medicinal chemistry letters.

[17]  Simon J F Macdonald,et al.  Cyclopropyl Carboxamides: A New Oral Antimalarial Series Derived from the Tres Cantos Anti-Malarial Set (TCAMS). , 2011, ACS medicinal chemistry letters.

[18]  Mitch Leslie,et al.  Infectious diseases. Drug developers finally take aim at a neglected disease. , 2011, Science.

[19]  José María Bueno,et al.  An Invitation to Open Innovation in Malaria Drug Discovery: 47 Quality Starting Points from the TCAMS. , 2011, ACS medicinal chemistry letters.

[20]  Ana Rodriguez,et al.  Activity In Vivo of Anti-Trypanosoma cruzi Compounds Selected from a High Throughput Screening , 2011, PLoS neglected tropical diseases.

[21]  M. Waterman,et al.  Sterol 14alpha-demethylase (CYP51) as a therapeutic target for human trypanosomiasis and leishmaniasis. , 2011, Current topics in medicinal chemistry.

[22]  L. Weiss,et al.  Chagas Disease Has Now Gone Global , 2011, PLoS neglected tropical diseases.

[23]  E. Chatelain,et al.  Drug discovery and development for neglected diseases: the DNDi model , 2011, Drug design, development and therapy.

[24]  J. Urbina.  Specific chemotherapy of Chagas disease: relevance, current limitations and new approaches. , 2010, Acta tropica.

[25]  J. Clayton.  Chagas disease: pushing through the pipeline , 2010, Nature.

[26]  Michelle R. Arkin,et al.  Image-Based High-Throughput Drug Screening Targeting the Intracellular Stage of Trypanosoma cruzi, the Agent of Chagas' Disease , 2010, Antimicrobial Agents and Chemotherapy.

[27]  C. Carneiro,et al.  Effects of Ravuconazole Treatment on Parasite Load and Immune Response in Dogs Experimentally Infected with Trypanosoma cruzi , 2010, Antimicrobial Agents and Chemotherapy.

[28]  Ian H. Gilbert,et al.  N-Myristoyltransferase inhibitors as new leads to treat sleeping sickness , 2010, Nature.

[29]  Ana Rodriguez,et al.  Identification of Three Classes of Heteroaromatic Compounds with Activity against Intracellular Trypanosoma cruzi by Chemical Library Screening , 2009, PLoS neglected tropical diseases.

[30]  J. Urbina,et al.  Activity of the New Triazole Derivative Albaconazole against Trypanosoma (Schizotrypanum) cruzi in Dog Hosts , 2004, Antimicrobial Agents and Chemotherapy.

[31]  A. Solari,et al.  Trypanosoma cruzi isolates from Chile are heterogeneous and composed of mixed populations when characterized by schizodeme and Southern analyses , 2004, Parasitology.

[32]  C. Carneiro,et al.  Chemotherapy with Benznidazole and Itraconazole for Mice Infected with Different Trypanosoma cruzi Clonal Genotypes , 2003, Antimicrobial Agents and Chemotherapy.

[33]  D. Loebenberg,et al.  Activities of the Triazole Derivative SCH 56592 (Posaconazole) against Drug-Resistant Strains of the Protozoan ParasiteTrypanosoma (Schizotrypanum) cruzi in Immunocompetent and Immunosuppressed Murine Hosts , 2000, Antimicrobial Agents and Chemotherapy.

[34]  J. Urbina.  Chemotherapy of Chagas’ disease: the how and the why , 1999, Journal of Molecular Medicine.

[35]  T. C. White,et al.  Induction of Resistance to Azole Drugs inTrypanosoma cruzi , 1998, Antimicrobial Agents and Chemotherapy.

[36]  Ximena Aguilera,et al.  Treatment of chronic Chagas' disease with itraconazole and allopurinol. , 1998, The American journal of tropical medicine and hygiene.

[37]  R. Kaminsky,et al.  The Alamar Blue assay to determine drug sensitivity of African trypanosomes (T.b. rhodesiense and T.b. gambiense) in vitro. , 1997, Acta tropica.

[38]  F. Lombardo,et al.  Computation of brain-blood partitioning of organic solutes via free energy calculations. , 1996, Journal of medicinal chemistry.

[39]  F. Buckner,et al.  Efficient technique for screening drugs for activity against Trypanosoma cruzi using parasites expressing beta-galactosidase , 1996, Antimicrobial agents and chemotherapy.

[40]  A. Romanha,et al.  Parasitological cure of acute and chronic experimental Chagas disease using the long-acting experimental triazole TAK-187. Activity against drug-resistant Trypanosoma cruzi strains. , 2003, International journal of antimicrobial agents.

[41]  A. Romanha,et al.  In vitro and in vivo activities of ravuconazole on Trypanosoma cruzi, the causative agent of Chagas disease. , 2003, International journal of antimicrobial agents.